Abstract
Beta cell loss and insulin resistance play roles in the pathogenesis of type 2 diabetes. Elevated levels of free fatty acids in plasma might contribute to the loss of beta cells. The objective of this study was to find a chemical that could protect against palmitate-induced beta cell death and investigate whether such chemical could improve hyperglycemia in mouse model of type 2 diabetes. Sodium fluorocitrate (SFC), an aconitase inhibitor, was found to be strongly and specifically protective against palmitate-induced INS-1 beta cell death. However, the protective effect of SFC on palmitate-induced cell death was not likely to be due to its inhibitory activity for aconitase since inhibition or knockdown of aconitase failed to protect against palmitate-induced cell death. Since SFC inhibited the uptake of palmitate into INS-1 cells, reduced metabolism of fatty acids was thought to be involved in SFC’s protective effect. Ten weeks of treatment with SFC in db/db diabetic mice reduced glucose level but remarkably increased insulin level in the plasma. SFC improved impairment of glucose-stimulated insulin release and also reduced the loss of beta cells in db/db mice. Conclusively, SFC possessed protective effect against palmitate-induced lipotoxicity and improved hyperglycemia in mouse model of type 2 diabetes.
Highlights
Type 2 diabetes (T2D) is developed when pancreatic beta cells fail to secrete sufficient amounts of insulin to meet the metabolic demand due to insulin resistance[1]
Full-size original blots are presented in supplementary Fig. S6. (d) Islet cells isolated from db/db mice were treated with 0.2 mM sodium fluorocitrate (SFC) in the presence of 0.4 mM palmitate for 48 h
To confirm that reduced cellular uptake of palmitate was essential for the protective effect of SFC on palmitate-induced lipotoxicity, we examined the effect of sulfo-N-succinimidyl oleate (SSO) as another inhibitor of fatty acid uptake on palmitate-induced INS-1 cell death[26]
Summary
Type 2 diabetes (T2D) is developed when pancreatic beta cells fail to secrete sufficient amounts of insulin to meet the metabolic demand due to insulin resistance[1]. Obesity-induced insulin resistance increases the level of free fatty acid in the plasma. It may induce beta cell failure through its toxicity to beta cells, thereby aggravating glycemic control[4,5]. Inhibition of acyl-CoA synthetase as the first step of fatty acid metabolism has been found to be protective against palmitate-induced lipotoxicity[6]. Lipid derivatives such as diacylglycerol, lysophosphatidic acids, and ceramide synthesized through augmented lipogenesis have been initially reported to play a role in fatty acid-induced lipotoxicity since increased fatty acid oxidation through treatment with AMP-activated kinase (AMPK). Beta cell preservation was determined through investigating insulin- and cleaved caspase 3-stained pancreatic islets
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